Lenalidomide, chemically (RS)-3-(4-Amino-1-oxo 1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione of formula (I),
is a pharmaceutically active compound used for the treatment of multiple myeloma and Myelodysplastic syndromes.
The compound was discovered by Celgene and is disclosed in EP925294. Lenalidomide is the active ingredient in the medicinal product sold under the brand name Revlimid®.
Lenalidomide exhibits polymorphism. WO2005023192 discloses crystalline forms of lenalidomide, its process of preparation, compositions comprising these crystalline forms and its use for treatment of diseases. Polymorph B is the most stable form and is present in the marketed tablets. Compositions comprising both amorphous and crystalline lenalidomide are also disclosed in this application. Other polymorphic forms of lenalidomide are disclosed in WO2011111053. The prior art thus teaches that lenalidomide crystallizes very easily. Moreover, it was experienced in our laboratory that polymorphic transitions of lenalidomide take place rather easily, especially in drug product.
Lenalidomide is slightly soluble in water. Conventional approaches to increase solubility consist on micronizing the API. Nevertheless, it was experienced in our laboratory that micronization of lenalidomide gave partially amorphous solid, which readily converts to other crystalline forms. It is known that generally the solubility of amorphous forms is higher compared to the solubility of crystalline forms. In view of this, it would be desirable to produce stable amorphous lenalidomide and to find a robust process for making such a stable amorphous lenalidomide.
WO2010054833 and WO2009114601 disclose solid dispersions containing amorphous lenalidomide.
It has been found that amorphous lenalidomide generates more impurities, especially oxidative impurities, if compared with the crystalline lenalidomide, making the use of amorphous lenalidomide in a commercial scale very difficult.
Revlimid® is in the market as a crystalline form, the market formulation, which has been submitted to extended stability studies does not contain an antioxidant.
WO2010061209 relates to new crystalline forms of lenalidomide in the description it is mentioned that preservatives and chelatings agents may be added to improve storage stability. This application however does not suggest that the replacement of crystalline lenalidomide for amorphous lenalidomide will result in additional stability problems.
Thus in view of the stability problems of amorphous lenalidomide, there is a need for pharmaceutical compositions comprising amorphous lenalidomide, or a pharmaceutically acceptable salt thereof, which are stable and suitable for use on a commercial scale.